Preserved Inhibitory Potency of GLP-1 on Glucagon Secretion in Type 2 Diabetes Mellitus

J Clin Endocrinol Metab. 2009 Dec;94(12):4679-87. doi: 10.1210/jc.2009-0921. Epub 2009 Oct 16.

Abstract

Objective: Glucagon-like peptide-1 (GLP-1) is insulinotropic, but its effect on the alpha-cell is less clear. We investigated the dose-response relationship for GLP-1-induced glucagon suppression in patients with type 2 diabetes (T2DM) and healthy controls.

Design: Ten patients with T2DM (duration of DM, 4 +/- 1 yr; glycosylated hemoglobin, 7.1 +/- 0.3%) were studied on 2 d, with stepwise increasing GLP-1 infusions (0.25, 0.5, 1.0, and 2.0 pmol x kg(-1) x min(-1)) (d 1) or saline (d 2) with plasma glucose (PG) clamped at fasting level. On d 3, patient PG was normalized overnight using a variable insulin infusion, followed by a 3-h GLP-1 infusion as on d 1. Ten healthy subjects were examined with the same protocol on d 1 and 2.

Results: We observed similar dose-dependent stepwise suppression of glucagon secretion in both patients and controls. Significant suppression was observed at a GLP-1 infusion rate of 0.25 pmol x kg(-1) x min(-1) (resulting in physiological plasma concentrations) as early as time 15 min in healthy controls and time 30 min in patients (d 1 and d 3). AUC for glucagon was significantly reduced on d 1 and 3 (1096 +/- 109 and 1116 +/- 108 3h x pmol/liter; P = NS) as compared to d 2 (1733 +/- 193 3h x pmol/liter; P < 0.01) in patients with T2DM. A similar reduction in AUC for glucagon was observed in healthy controls [1122 +/- 186 (d 1) vs. 1733 +/- 312 3h x pmol/liter (d 2); P < 0.001].

Conclusions: The diabetic alpha-cell appears to be highly sensitive to the inhibitory action of GLP-1 both during high and near-normalized PG levels, but responds with a short, nevertheless significant delay.

Trial registration: ClinicalTrials.gov NCT00862589.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blood Glucose / metabolism
  • C-Peptide / blood
  • Diabetes Mellitus, Type 2 / metabolism*
  • Dose-Response Relationship, Drug
  • Female
  • Glucagon / metabolism*
  • Glucagon-Like Peptide 1 / administration & dosage
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucagon-Secreting Cells / drug effects
  • Glucose Tolerance Test
  • Humans
  • Infusions, Intravenous
  • Insulin / blood
  • Male
  • Middle Aged

Substances

  • Blood Glucose
  • C-Peptide
  • Insulin
  • Glucagon-Like Peptide 1
  • Glucagon

Associated data

  • ClinicalTrials.gov/NCT00862589